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European Perspectives on Advanced Therapy Medicinal Products(ATMP)
PMDA 2nd International Symposium on Biologics
Tokyo, 17th January, 2008
P.ZORZI
Department for Evaluation of Biologics
PZ2
OVERVIEW
•Products defined as ATMP
•European Bodies and Procedures
•EC Regulation on ATMP (1394/2007/EC -13 Nov 2007)
•Cell/Tissues at National level : ex of France•National authorizations•Clinical trials•Biovigilance
PZ3
Products Defined as ATMP
•Cell therapy Medicinal Products
•Gene Therapy Medicinal Products
•Tissues engineered Medicinal Products
Centralized european procedures mandatory
PZ4
OVERVIEW
•Products defined as ATMP
•European Bodies and Procedures
•EC Regulation on ATMP (1394/2007/EC -13 Nov 2007)
•Cell/Tissues at National level : ex of France•National authorizations•Clinical trials•Biovigilance
PZ5
LondonEMEA
•MA/Scientificopinion
•Scientificguidances
BrusselsEU
•MA /administrative decision•Pharma. legislationDirectives
ParisAFSSAPS
PZ6
EU Bodies and ProceduresEuropean Medicines Agency (EMEA)
• 1995: European Agency for the Evaluation of Medicinal Products (EMEA)
• 2004 (EC No 726/2004): European Medicines scientific resources for Agency (EMEA)
• Coordinates the evaluation, supervision and pharmacovigilance of medicinal products
• Scientific resources: 27 member states
• Over 4000 European experts
• ~440 staff members
http://www.emea.eu.int/
PZ7
EU Bodies and Procedures European Medicines Agency (EMEA)
EMEAScientific
Committees
CHMPCommittee for Medicinal Product for Human use
CVMPCommittee for Medicinal Product for Veterinary
use
COMPCommittee of Orphan
Medicinal Product
HCMPCommittee for
Herbal Medicinal Product
PZ8
EU Bodies and Procedures European Medicines Agency (EMEA)
•CHMP• Responsible for the scientific opinions (Q, S, E)• 1 representative for each member state • Chairman (3 years)• Working groups (permanent, ad’hoc)
CHMPWorking Parties
BiotechnologyWorking Party
PharmacovigilanceWorking Party
QualityWorking Party
Blood and PlasmaWorking Party
Efficacy Working Party
Scientific Advice
Gene TherapyWorking Party
InspectorWorking Party
Cell BasedWorking Party
VaccineWorking Party
‘Biosimilar’Working Party
PZ9
Eur. Com. (Brussels)
1 MA all EU
1 SPC, labelling, package
leaflet
National
Harmonized SPC all EU
Ex:commercialized in 4+1 MS
National Administrative Decision
CHMP/ EMEA (London)Each member State
Ex : 4 approval, 2 rejectionNational
Scientific Opinion
1
EMEA
1 each
Concerned Member state
Ex : 6 CMS
NationalDossier
Submission
CentralizedMutual RecognitionRecognition of first country
approval
National
EU Bodies and Procedures Registration Procedures
PZ10
European Union adopts legislation in the form ofDirectives and Regulations
• Directives require member states to implement theirprovisions nationally for the benefit of Europe as a whole.
• Regulations directly implement EU policy in memberstates without the need for member states to enact theirown legislation.
EU Bodies and Procedures European Commission
PZ11
OVERVIEW
•Products defined as ATMP
•European Bodies and Procedures
•EC Regulation on ATMP (1394/2007/EC -13 Nov 2007)
•Cell/Tissues at National level : ex of France•National authorizations•Clinical trials•Biovigilance
PZ12• autologous products • allogeneic products
Ref. : Joint Research Centre, European Commission, 2003 (see also impact assessment of the proposal)
Advanced Therapies Medicinal ProductsDivergent National Systems
PZ13
•Because of the novelty, complexity and technical specificity, need to have a specially tailored and harmonized rules to ensure free movement of those products within the community
•ATMP
• Products already covered by European regulations :
• Gene therapy MP
• Cell therapy MP
• Newly included
• Tissue engineered MP
• Combination product containing human viable cells/tissues and
med devices : regulated under this new regulation
Advanced Therapies Medicinal ProductsNeed for harmonized regulatory framework
PZ14
Medicinal Products
Directive 2004/23/CEDonnor selection (2006/17)
Establishment., GP, traceability (2006/8
New ChemicalEntity
MP
BiologicalMP
RegulationAdvanced TherapyMedicinal Products
1394/2007/EC
Tissue Engineered
Products
cell/tissue not ATMP
MANational
Community Code Directive 2001/83/EC
(Annex 2003/63/EC)
Tissues/Cells
Med ProductsAnnex 1
CellTh
Gene Th
Pharmacovigilance Biovigilance (France)
MACentralized or National
MACentralized mandatory
Advanced Therapies Medicinal ProductsRegulatory Framework Overview
PZ15
•Somatic Cell Therapy MP (from Dir 2001/83/EC) under revision
Autologous, allogeneic or xenogeneic living cells,
biological characterictics substantially modified, altered
to obtain a therapeutic, diagnostic or preventive effect through
metabolic, pharmacologic and immunological means
•Gene Therapy MP (from Dir 2001/83/EC) under revision
Transfer, to be performed in vivo or ex vivo of a prophylactic, diagnostic
or therapeutic gene to human or animal cells.
Gene transfer involves an expression system contained in a delivery
system known as a vector, which can be of viral as well as non viral
origin
Advanced Therapies Medicinal ProductsDefinitions and Scope
PZ16
•Tissue Engineered Product (Newly covered by the Regulation)
contains cell or tissues of human or animal origin
cells may be viable or non viable
may also contain additional substances :cellular products,
biomolecules, biomaterials, chemical substances, scaffold, matrices
• TEP means a product that :
contains or consists of engineered cells or tissues
is presented as having properties for, or is used in, or administer to
human being with a view to regenerating, repairing or replacing a
human tissue
• Combination product containing viable cells and medical devices :
regulated under this new regulation (not any more under med device
directives)
Advanced Therapies Medicinal ProductsDefinitions and Scope
PZ17
• Excluded from the definition TEP
Product containing or consisting of non viable cells/tissues, which do
not act principally by pharmacological, immunologically or metabolic
actions
• Excluded from the scope of the regulation
ATMP prepared in a non-routine basis,
Used within the same member state, in a hospital, for an individual
patient
In that case : manufacturing is authorized by the MS. Traceability,
pharmacovigilance requirements, specific quality standards at
national level should be equivalent to the regulation
•Case of Embryonic stem cells and animal cells
The use (or not) of medicinal products containing such cells remainsa national decision (ex. for ethical reasons…)
Advanced Therapies Medicinal ProductsDefinitions and Scope
PZ18
•No marketing without prior authorization
•Centralized procedure mandatory
•Evaluation by EMEA
•Demonstration of Quality, Safety & Efficacy
•Dossier : same as medicinal product (CTD applicable, with
technical adaptations)
•Post-authorization vigilance
Advanced Therapies Medicinal ProductsKey principles of the proposal
PZ19
•Pre-authorization requirements
• When Medical Device present : Compliance with ‘Essential
Requirements’ as defined in the EU Directives on Medical Devices
• Specific guidelines currently under discussion
• GMP (Good Manufacturing Practice)
• GCP (Good Clinical Practice)
• Specific rules for labeling/packaging
•Post-authorization requirements
• Follow-up of efficacy, adverse reactions and risk management
• Traceability
Advanced Therapies Medicinal ProductsTechnical Requirements
PZ20
General provisions
•Scientific Advice:
• 90% fee reduction for SMEs, 65% for others
• No limit in time
•Scientific recommendation on advanced therapy classification: 60days
Advanced Therapies Medicinal ProductsCompetitiveness Aspects
PZ21
Specific provisions (SMEs, hospitals)
•SMEs: EARLY STAGE OF DEV / Certification by EMEA of quality and non-clinical data
• Not a marketing authorization
• Not ‘legally binding’ for the Agency
• Mostly quality and, where available, non-clinical data
•Additional Fee reduction if applicant is SME or hospital and canprove there is a particular public health interest in the Community
• 50% fee reduction on MA fee
• 50% post-authorization activities during one year
• Applies only during transitional period
Advanced Therapies Medicinal ProductsCompetitiveness Aspects
PZ22
•Transitional period: products already on the market <30 Dec 2008 (national or Europe)
• For cell and Gene Therapy MP : shall comply < 30 Dec 2011
• For Tissue Engineered MP : shall comply <30 Dec 2012
•During transitional period, no MA fee for upgrade of ‘national products’
European Commission
http://ec.europa.eu/enterprise/pharmaceuticals/advtherapies/index.htm
Advanced Therapies Medicinal ProductsEntry into Force
PZ23
http://www.emea.europa.eu/htms/human/humanguidelines/biologicals.htm
• Human Cell Based MP CPMP/BWP/410869/06 (en consultation)
• Points to Consider on Xenogeneic Cell Therapy MP CPMP/1199/02 (Nov 2000)
• Gene Therapy Product Quality Aspects in the Production of Vectors and Genetically
Modified Somatic Cells
• Environmental Risk Assessments for Medicinal Products containing, or consisting of,
Genetically Modified Organisms (GMOs) (EMEA/CHMP/473191/06)
• …..
Advanced Therapies Medicinal ProductsEMEA Technical Guidances
PZ24
OVERVIEW
•Products defined as ATMP
•European Bodies and Procedures
•EC Regulation on ATMP (1394/2007/EC -13 Nov 2007)
•Cell/Tissues at National level : ex of France•National authorizations•Clinical trials•Biovigilance
PZ25
French organizationAfssaps
Agence française de sécuritésanitaire des produits de santé
(French Health Products Safety Agency)
•National Agency•~900 employees•~2000 experts
http://afssaps.sante.fr/
PZ26
Afssaps Siège Social et Laboratoires
143/147, boulevard Anatole France93285 SAINT-DENIS CEDEX
01.55.87.30.00www.afssaps.sante.fr
Afssaps Laboratoires321, avenue Jean Jaurès
69007 LYON
Afssaps Laboratoires635, rue de la Garenne
37740 Vendargues
PARIS
LYON
MONTPELLIER
French OrganizationAfssaps
PZ27
Cells/TissuesFrench Regulatory Framework
Main Laws•GMO (92) - Bioethical (94, revised each 5 years) - DMOSS (96) -
"Afssaps"(98)
•Decree 1st Oct 2001
Afssaps : Autority Responsible
•Cellular Therapy / Gene Therapy products
•« Ancillary » products
•Tissues, Organs
PZ28
Afssaps Authorizations
• Establishments
• Private Cies : pharmaceutical establishments
• Public organisms
• Products
• Proprietary medicinal products
• Non proprietary med products
• Clinical trials
Afssaps Responsabilities• Inspection
• Biovigilance
• Quality controls
28
Cells/TissuesAfssaps Authorizations and Responsabilities
PZ29
All types of products covered
• Simple Processes• Autologous HSC frozen/ stored /shipped prior re-administration
• Complex Processes• Cell therapy : selection, propagation, differentiation, incorporation
into a matrix...• Gene therapy i.e. viral vectors : banking system, culture,
purification and lyophilisation
• Proprietary medicinal products • Recombinant viral vectors• Allogeneic fibroblasts (diabetic fore-foot ulcer)
• Non proprietary medicinal products• Autologous : Hematopoietic stem cell (cancer), Keratinocytes (burned
patients)• Allogeneic : pancreatic cells (diabetes patients), fetal neurons (Parkinson,
Huntington)
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Cells/TissuesAfssaps Authorizations and Responsabilities
PZ30
•Cell therapy
• Hematopoietic stem cells (allogeneic, autologous) in 35 Establishments
(cell banks)
• Other cells : only clinical trials
•Gene therapy
• No product on the market in France. Only clinical trials
•Tissues
• Establishments authorized : 40
• Products authorized (or ongoing) :Corneas, Bones (cryopreserved or viro
inactivated), Skin, Cardiac valves, vessels
• Clinical trials : Amniotic membrane in vascular ulcer, trachea replacing
aorta, ovarian tissue autotransplant (chimotherapy situation)
•Organs
• Clinical Trials : Face transplantation, Hand transplantation
Cells/TissuesAfssaps Authorizations and Responsabilities
PZ31
Same manufacturing steps•Starting materials
•Bulk active ingredient-Finished medicinal product
Same requirements•QA system
•Starting materials (quality/traceability)•Process validated and reproducible
•QC of the product to be administered
Pharma. Establishmentsor non Pharma. Est.(public/private)
Proprietary
or
non Propr
Med. Prod.
Cells/TissuesAfssaps Authorizations and Responsabilities
PZ32
Concept of viral safety based on 3 complementary levels
1.Quality of starting material and other raw materials (ie
ancillary products PTA)
2.Efficacy of the production process to eliminate/inactivate
viruses
3.Virological in-process controls
The respective importance of each parameter is related to the type of product
Cells/TissuesViral Safety
PZ33
Benefit / risk
- If any-Eliminat°/inactiv°
-Validation (spik.)
-Eliminat°/inactiv°
-Validation (spik.)Process
-Testing (pool)-Testing (harvest)Product/
intermediate
-Donor selection
-Ancillary products
-Donor selection
-Tests for infection
-Cell banks
-Bov.serumStarting mat.
Reagents
Cell Therapy/
Tissues
Plasma DMPRec Products
Cells/TissuesViral Safety
PZ34
European Directive 2006/17/CE
Décret et arrêté du 21/12/05
Arrêté du 14/01/04
Regulatory Framework
HIV ½ Ab + AgP24 or RNA-HIV 1
HCV Ab
AgHBs + Anti-HBc Ab + Anti-HBs Ab Cells / TissuesHTLV I/II Ab
T. Pallidum (serology)
CMV Ab
EBV Ab Cells onlyToxoplasmosis serology
Biological selection
Exclusion criteria regarding transmissible infectionsClinical selection
Cells/TissuesViral Safety
Donor Selection
PZ35
Ancillary products : Examples
- Foetal bovine serum (FBS)
- Trypsin
- Milk derivatives (casein…)
- Insulin
- Cytokines
- Amino-Acids (component of some culture media…)
- Human albumin or transferrin
……
Cells/TissuesViral Safety
PZ36
Ancillary products : Documentation to be submitted
Conventional viruses aspects
- quality of starting material (geographical origin, species, tissue), viral
testing if appropriate
- main steps of the manufacturing process dedicated to viruses
inactivation/removal (ie. autoclaving)
TSE aspects (for products derived from ruminants)
- CEP TSE delivered by EDQM should be provided or appropriate
documentation according NFG EMEA/410/01
Cells/TissuesViral Safety
PZ37
OVERVIEW
•Products defined as ATMP
•European Bodies and Procedures
•EC Regulation on ATMP (1394/2007/EC -13 Nov 2007)
•Cell/Tissues at National level : ex of France•National authorizations•Clinical trials•Biovigilance
PZ38
•Since 1996 ~ 230 trials submitted
• Sponsors
• 80% public establishments
• Others : pharmaceutical companies
•Type of cells
• 60% Hematopoietic stem cells
• 75% autologous
Clinical Trials in France Cell Therapy
PZ39
• Haematopoietic stem cells :marrow, peripheral, placental
• Hematology : lymphoma, leukemia (ALL, AML…)
• Cardiomyoplasty, lower limb arteriopathy
• Immune cells : Macrophages, dendritic, dexosomes, T cells
• Immunotherapy of cancers (melanoma, lung, kidney, ovarian…) and infectious
diseases
• Chondrocytes
• Knee articular cartilage injuries
• Keratinocytes/ Fibroblasts
• Veinous ulcer, diabetic forefoot ulcer, second and third degree burns
• Nervous cells
• Parkinson, huntington diseases
• Myoblasts
• Severe postinfarction left ventricular dysfunction
• Pancreatic islets
• Diabetis mellitus
Clinical Trials in FranceCell Therapy
PZ40
•Since 1993 ~ 70 trials submitted
•Sponsors
• 1/3 public establishments
• 2/3 pharmaceutical companies
•vectors
• Viral : Retrov, Adenov, Lentiv, AAV, Pox
• Non viral : Plasmids
•Strategies
• ¾ In vivo - ¼ Ex vivo
•Clinical Phase
• Phase I-II mostly (phase III <5)
Clinical Trials in France Gene Therapy
PZ41
OVERVIEW
•Products defined as ATMP
•European Bodies and Procedures
•EC Regulation on ATMP (1394/2007/EC -13 Nov 2007)
•Cell/Tissues at National level : ex of France•National authorizations•Clinical trials•Biovigilance
PZ42
To supervise and assess :
the risk of event and events in relation with products and activities (procurement, processing, testing, storage...)
Examples : microbiological contamination, incomplete serological data, viral inactivation, process failure……
adverse reactions in the living donor or patient
Examples : allergic reaction, keratitis, fever, infectious diseases, anaphylactic reaction, neurological disorders
Biovigilance Scope
PZ43
Biovigilance
Activities
ProcurementDonation
Shipment
DistributionProcessing
Importation
Exportation
GraftAdministration
Testing
Patients follow-up
Donorsselection
Storage
Preservation
PZ44
Products included in the biovigilance field
Products excluded from the biovigilance field
• Human organs, tissues or cells intended for therapeutic application as well as ancillary products
• Cellular therapy preparations
• Medical devices including human derived products
• Ancillary products
• Gamets (Biomedecine Agency)
• Labile blood products
• Cell and gene therapy products requiring marketing authorization
• Other medical devices
• Human derived medicinal products (blood derived medicinal products, « extractive protein »)
• In vitro diagnosis devices
BiovigilanceProducts Covered
PZ45
In Establishments in charge of :
procurement or donation : public or private health establishments, blood establishments,…
processing, testing, preservation, storage, distribution, importation, exportation
tissue and cell establishmentsmanufacturer of ancillary products …
graft and administration : public or private health establishments…
Biovigilance Correspondants
PZ46
No regional level
Wide range of application fields
variety of products and activities
variety of interlocutors
Not only one manufacturer (except for organs)
Wide variety of medical practices
Few notifications, far less than in Haemovigilance : nb events or reactions
Cells/Tissues/organs ~ 4200 organs grafted,
3000 autologous HSC, ~ 170 /year1200 allogeneic HSC, 20 000 tissues
Labile Blood Products ~ 2 500 000 distributed ~ 7600/year
Biovigilance Specificities
PZ47
ensures organization of the Biovigilance system at a national level
- coordination of Biovigilance local contacts network
- assessement of Biovigilance notifications
- coordination of national Biovigilance actions (alerts, informations, recommendations..)
ensures that procedures are implemented in tissues establishment and in health establishments
the aim is to improve the safety of human organs, tissues, cells and ancillary products
Biovigilance Afssaps : Competent Authority
PZ48
1-SARs with organs
very likely melanoma disease transmission by organs from one donor to the 4 recipients (1st case described in France)
bibliographic research (similar cases described) and meeting with experts, ABM and Afssaps : official recommendations to health professionals
2-SARs with cell preparations : after autologous HSC infusion
assessment by experts : reactions from multicausal origin (disease of the patient, chemotherapy, composition of graft, flow infusion,…)
first hypothesis : SARs could be related to the amount of granulocytes in the aphaeresis product
information of the professionals concerned
Biovigilance Examples
PZ49
3-Events with ancillary products
quality defect of a cornea preservation solution (abnormal color of the medium)
no contamination, not batch-related, occurs only after thawing in the surgery block : some cornea lost
investigations (manufacturer + Afssaps) : the packaging was not adapted and moreover not in accordance with the specifications
a new prototype of transport is proposed : event over
Biovigilance Examples
PZ50
300 biovigilance correspondants appointed
notification form
working groups
methodological aspects : guide of biovigilance, annual report format
scientific aspects : melanoma, adverse reactions after HSC infusion
national commission : 1st meeting on the 21th March 2007
regional meeting on site with professionals of the network : in
progress
Biovigilance Implementation after 4 years
PZ51
Conclusions
•The framework published in Europe November 2007 for Advanced Therapy Medicinal Products will allow an harmonized marketing authorization throughout Europe for these products aiming at facilitating free circulation through member states. It will guarantee a high level of health protection for European patients
• EMEA is setting up guidelines to harmonize evaluation criteria
• For products which are outside the scope of the regulation, they will continue to be regulated at national level with still possible divergenciesbetween members states. In France, the legal framework makes theAfssaps the authority responsible for all cells and tissues, even if they do not respond to the definition of Medicinal products (called “preparations”)